Habitat use,but not gene flow,is influenced by human activities in two ecotypes of Egyptian fruit bat (Rousettus aegyptiacus)

Understanding the ecological, behavioural and evolutionary response of organisms to changing environments is of primary importance in a human‐altered world. It is crucial to elucidate how human activities alter gene flow and what are the consequences for the genetic structure of a species. We studied two lineages of the Egyptian fruit bat (Rousettus aegyptiacus) throughout the contact zone between mesic and arid Ecozones in the Middle East to evaluate the species' response to the growing proportion of human‐altered habitats in the desert. We integrated population genetics, morphometrics and movement ecology to analyse population structure, morphological variation and habitat use from GPS‐ or radio‐tagged individuals from both desert and Mediterranean areas. We classified the spatial distribution and environmental stratification by describing physical–geographical conditions and land cover. We analysed this information to estimate patch occupancy and used an isolation‐by‐resistance approach to model gene flow patterns. Our results suggest that lineages from desert and Mediterranean habitats, despite their admixture, are isolated by environment and by adaptation supporting their classification as ecotypes. We found a positive effect of human‐altered habitats on patch occupancy and habitat use of fruit bats by increasing the availability of roosting and foraging areas. While this commensalism promotes the distribution of fruit bats throughout the Middle East, gene flow between colonies has not been altered by human activities. This discrepancy between habitat use and gene flow patterns may, therefore, be explained by the breeding system of the species and modifications of natal dispersal patterns.     

Vascular endothelial dysfunction associated with elevated serum homocysteine levels in rat adjuvant arthritis: effect of vitamin E administration

We aimed to study the alterations in serum homocysteine levels and endothelium-dependent and -independent vascular relaxant responses in adjuvant-induced arthritis of the rat and to determine the effects of vitamin E administration on these changes. Arthritis was induced by a single intradermal injection of Freund's complete adjuvant into the paw. 26 days after the induction of arthritis, serum homocysteine levels and relaxant responses to acetylcholine and sodiumnitroprusside in thoracic aortas were evaluated. The relaxant responses to acetylcholine were decreased in aortas from arthritic rats, whereas the responses to sodiumnitroprusside were not significantly different when compared to the aortas from control rats. A significant increase was observed in serum homocysteine levels of the arthritic rats in comparison to those of controls. Vitamin E administration (100 mg/kg/day, i.m. for 26 days) to arthritic rats resulted in a significant increase in endothelium-dependent aortic responses to acetylcholine and a significant decrease in serum homocysteine levels with respect to the non-treated arthritic rats. However, in healthy rats, vitamin E treatment significantly decreased the acetylcholine-induced relaxant responses. We conclude that adjuvant-induced arthritis in the rat is associated with increased serum homocysteine levels and this is accompanied by a reduction in endothelium-dependent vascular responses in the thoracic aortas. Vitamin E treatment leads to normalization of the increased serum homocysteine levels and improves the endothelium-dependent relaxant responses in this experimental model.     

A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing

Proteolytic processing of the transmembrane domain of the amyloid precursor protein (APP) is a key component of Alzheimer's disease pathogenesis. Using C-terminally tagged APP derivatives, we have identified by amino-terminal sequencing a novel cleavage site of APP, at Leu-49, distal to the gamma-secretase site. This was termed -cleavage. Brefeldin A treatment and pulse-chase experiments indicate that this cleavage occurs late in the secretory pathway. The level of -cleavage is decreased by expression of presenilin-1 mutants known to impair Abeta formation, and it is sensitive to the gamma-secretase inhibitors MDL28170 and L-685,458. Remarkably, it shares similarities with site 3 cleavage of Notch-1: membrane topology, cleavage before a valine, dependence on presenilins, and inhibition profile.     

In vitro gamma-secretase cleavage of the Alzheimer's amyloid precursor protein correlates to a subset of presenilin complexes and is inhibited by zinc

The gamma-secretase complex mediates the final proteolytic event in Alzheimer's disease amyloid-beta biogenesis. This membrane complex of presenilin, anterior pharynx defective, nicastrin, and presenilin enhancer-2 cleaves the C-terminal 99-amino acid fragment of the amyloid precursor protein intramembranously at gamma-sites to form C-terminally heterogeneous amyloid-beta and cleaves at an epsilon-site to release the intracellular domain or epsilon-C-terminal fragment. In this work, two novel in vitro gamma-secretase assays are developed to further explore the biochemical characteristics of gamma-secretase activity. During development of a bacterial expression system for a substrate based on the amyloid precursor protein C-terminal 99-amino acid sequence, fragments similar to amyloid-beta and an epsilon-C-terminal fragment were observed. Upon purification this substrate was used in parallel with a transfected source of substrate to measure gamma-secretase activity from detergent extracted membranes. With these systems, it was determined that recovery of size-fractionated cellular and tissue-derived gamma-secretase activity is dependent upon detergent concentration and that activity correlates to a subset of high molecular mass presenilin complexes. We also show that by changing the solvent environment with dimethyl sulfoxide, detection of epsilon-C-terminal fragments can be elevated. Lastly, we show that zinc causes an increase in the apparent molecular mass of an amyloid precursor protein gamma-secretase substrate and inhibits its cleavage. These studies further refine our knowledge of the complexes and biochemical factors needed for gamma-secretase activity and suggest a mechanism by which zinc dysregulation may contribute to Alzheimer's disease pathogenesis.     

Nicastrin expression in mouse peripheral tissues is not co-ordinated with presenilin and is high in muscle

Nicastrin was the first binding partner of presenilin (PS) shown to be a critical component of the presenilin/gamma-secretase complex essential in development and differentiation, and in generation of Alzheimer's disease Abeta amyloid peptide. To investigate the function of this glycoprotein, we compared nicastrin and presenilin protein expression in various mouse tissues. Western blot analysis of PS1, PS2 and nicastrin indicates their expression levels are not coordinated. In adult mouse, nicastrin is highly expressed in muscle membranes, whereas presenilin levels are very low. By Blue Native electrophoresis, a PS1 complex of 400 kDa was detected in lung, brain, thymus and heart; nicastrin was also detected as a 400-kDa complex in brain but in muscle it was detected with a complex mobility of 240 and 290 kDa, suggesting association with alternate protein complexes. Immunocytochemistry confirms strong intracellular expression of nicastrin in skeletal muscle and blood vessel smooth muscle. These findings suggest a function for nicastrin in muscle other than participation in the gamma-secretase complex.     

Multistep phosphorylation systems: tunable components of biological signaling circuits

Multisite phosphorylation of proteins is a powerful signal processing mechanism that plays crucial roles in cell division and differentiation as well as in disease. We recently demonstrated a novel phenomenon in cell cycle regulation by showing that cyclin-dependent kinase–dependent multisite phosphorylation of a crucial substrate is performed sequentially in the N-to-C terminal direction along the disordered protein. The process is controlled by key parameters, including the distance between phosphorylation sites, the distribution of serines and threonines in sites, and the position of docking motifs. According to our model, linear patterns of phosphorylation along disordered protein segments determine the signal-response function of a multisite phosphorylation switch. Here we discuss the general advantages and engineering principles of multisite phosphorylation networks as processors of kinase signals. We also address the idea of using the mechanistic logic of linear multisite phosphorylation networks to design circuits for synthetic biology applications.     

THE CHANGING PACE OF INSULAR LIFE: 5000 YEARS OF MICROEVOLUTION IN THE ORKNEY VOLE (MICROTUS ARVALIS ORCADENSIS)

Island evolution may be expected to involve fast initial morphological divergence followed by stasis. We tested this model using the dental phenotype of modern and ancient common voles (Microtus arvalis), introduced onto the Orkney archipelago (Scotland) from continental Europe some 5000 years ago. First, we investigated phenotypic divergence of Orkney and continental European populations and assessed climatic influences. Second, phenotypic differentiation among Orkney populations was tested against geography, time, and neutral genetic patterns. Finally, we examined evolutionary change along a time series for the Orkney Mainland. Molar gigantism and anterior‐lobe hypertrophy evolved rapidly in Orkney voles following introduction, without any transitional forms detected. Founder events and adaptation appear to explain this initial rapid evolution. Idiosyncrasy in dental features among different island populations of Orkney voles is also likely the result of local founder events following Neolithic translocation around the archipelago. However, against our initial expectations, a second marked phenotypic shift occurred between the 4th and 12th centuries AD, associated with increased pastoral farming and introduction of competitors (mice and rats) and terrestrial predators (foxes and cats). These results indicate that human agency can generate a more complex pattern of morphological evolution than might be expected in island rodents.     

Determination of sex from the tibia

Determination of sex from the tibial shaft as well as the entire bone itself has not been generally investigated by osteologists . This paper is an attempt to fulfill this need. The purpose is to determine sex from both the complete tibia and the shaft at the nutrient foramen level. The sample was obtained from the Terry Collection and included 159 specimens of whites and blacks. The tibial length, and circumference, anteroposterior, and transverse measurements at the nutrient foramen level were analyzed by means of step-wise discriminant function analysis. It was found that the circumference alone could give, on the average, 80% accuracy in determining sex. The addition of other dimensions to the function increased the accuracy by about 4%. Comparisons of this study with those on the femur indicated that sexual dimorphism in the tibia was a result not only of the general growth and musculo-skeletal activity, but also of the genetic structure of the population, i.e., racial variation.